Intermediate for production of nucleoside analog and method for producing the same

Abstract

A compound represented by the general formula (III) which serves as an intermediate of an oligonucleotide analog having stable and excellent antisense or antigene activity or having excellent activity as a detection reagent (probe) for a specific gene or as a primer for the initiation of amplification of a specific gene can be produced at high yields regardless of the type of nucleobase by a method comprising reacting a compound represented by the general formula (II) or a salt thereof with a trimethylsilylated compound obtained from a compound represented by the general formula (IVb), wherein X, Y, Z, A, R, and B are as defined in claim 1.

The invention claimed is: 
     
       1. A method of producing a compound of formula (III): 
       
         
           
           
               
               
           
         
         or a salt thereof, comprising 
         reacting a compound of formula (IVb): 
       
       
         
           
           
               
               
           
         
         with a trimethylsilylating agent to produce a trimethylsilylated compound; and 
         reacting the trimethylsilylated compound with a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein 
         A is an alkylene group having 1 to 4 carbon atoms; 
         B is a purin-9-yl group or a purin-9-yl group having one or more substituents selected from group α; 
         X, Y, and Z are each independently a protective group for the hydroxy group; 
         R is a silyl protective group; 
         R 4 , R 5 , and R 6  are each independently a hydrogen atom, a hydroxy group, a protected hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a mercapto group, a protected mercapto group, an alkylthio group having 1 to 4 carbon atoms, an amino group, a protected amino group, an amino group substituted by one or more alkyl groups having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, or a halogen atom; and 
         group α is a hydroxy group, a protected hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a mercapto group, a protected mercapto group, an alkylthio group having 1 to 4 carbon atoms, an amino group, a protected amino group, an amino group substituted by one or more alkyl groups having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, or a halogen atom. 
       
     
     
       2. The method of  claim 1 , wherein X is a methyl group substituted by 1 to 3 aryl groups, or a methyl group substituted by 1 to 3 aryl groups wherein the aryl rings are each substituted by a lower alkyl, lower alkoxy, halogen, or cyano group. 
     
     
       3. The method of  claim 1 , wherein X is a benzyl group, a p-methoxybenzyl group, a dimethoxytrityl group, or a monomethoxytrityl group. 
     
     
       4. The method of  claim 1 , wherein Y is a methyl group substituted by 1 to 3 aryl groups, or a methyl group substituted by 1 to 3 aryl groups wherein the aryl rings are each substituted by a lower alkyl, lower alkoxy, halogen, or cyano group. 
     
     
       5. The method of  claim 1 , wherein Y is a benzyl group, a β-naphthylmethyl group, or a p-methoxybenzyl group. 
     
     
       6. The method of  claim 1 , wherein Z is an aliphatic acyl group having 2 to 4 carbon atoms. 
     
     
       7. The method of  claim 1 , wherein Z is an acetyl group. 
     
     
       8. The method of  claim 1 , wherein A is a methylene group or an ethylene group. 
     
     
       9. The method of  claim 1 , wherein A is a methylene group. 
     
     
       10. The method of  claim 1 , wherein B is a 6-aminopurin-9-yl group, a 6-aminopurin-9-yl group with the amino group protected, a 2,6-diaminopurin-9-yl group, a 2-amino-6-chloropurin-9-yl group, a 2-amino-6-chloropurin-9-yl group with the amino group protected, a 2-amino-6-fluoropurin-9-yl group, a 2-amino-6-fluoropurin-9-yl group with the amino group protected, a 2-amino-6-bromopurin-9-yl group, a 2-amino-6-bromopurin-9-yl group with the amino group protected, a 2-amino-6-hydroxypurin-9-yl group, a 2-amino-6-hydroxypurin-9-yl group with the amino group protected, a 2-amino-6-hydroxypurin-9-yl group with the amino group and hydroxy group protected, a 6-amino-2-methoxypurin-9-yl group, a 6-amino-2-chloropurin-9-yl group, a 6-amino-2-fluoropurin-9-yl group, a 2,6-dimethoxypurin-9-yl group, a 2,6-dichloropurin-9-yl group, or a 6-mercaptopurin-9-yl group. 
     
     
       11. The method of  claim 1 , wherein B is a 6-benzoylaminopurin-9-yl group, an adeninyl group, a 2-isobutyrylamino-6-hydroxypurin-9-yl group, or a guaninyl group. 
     
     
       12. The method of  claim 1 , wherein R is a tri-lower alkylsilyl group, a monoaryl di-lower alkylsilyl group, or a diaryl mono-lower alkylsilyl group. 
     
     
       13. The method of  claim 1 , wherein R is a monoaryl di-lower alkylsilyl group or a diaryl mono-lower alkylsilyl group. 
     
     
       14. The method of  claim 1 , wherein R is a t-butyldiphenylsilyl group.